1. Field of the Invention
The present invention relates generally to methods and compositions for the enhancement of cellular proliferation and the treatment of wounds and other disorders. More specifically, the invention relates to the use of neuropeptides for wound treatment in general and corneal wound treatment in particular.
Traumatic injury and disease can cause damage to the skin, tissue, and body organs which requires cellular regeneration for healing. Accidental injuries such as cuts, abrasions, burns, and intentional surgical procedures result in wounds which can affect large areas of the skin or affected body organs and can require lengthy periods to heal. Long healing times are a particular problem with denervated regions of the extremities and with wounds on sensitive areas, such as corneal wounds, which are difficult to treat over prolonged periods. For these reasons, it would be desirable to provide methods and pharmacological agents which can be used to promote rapid healing of wounds and other injuries to the skin, tissue, and body organs.
A variety of cellular growth promoting hormones have been identified which can enhance cellular proliferation which have been used in wound treatment, including corneal wound treatment. Exemplary growth promoting hormones include epidermal growth factor, transforming growth factor .beta., insulin-like growth factor, platelet-derived growth factor, and the like. While use of these hormones continues to hold promise, no one growth promoting agent can be optimal for all situations. Thus, it would be desirable to identify additional substances and compositions which have therapeutic value as growth promoting agents, and it would be further desirable to identify substances and compositions which are capable of enhancing or modulating the effect of these and other growth promoting substances.
In addition to cellular proliferation, wound healing requires the elaboration of excellular matrices and development of cellular attachment mechanisms in order to achieve normal tissue morphology. For example, the formation of fibronectin is an important function in normal wound healing. Without sufficient expression of fibronectin and other cellular matrix substances, regenerated tissue can have an abnormal morphology. Thus, it would be desirable to identify substances and compositions which could promote such additional wound healing responses.
For the above reasons, it is an object of the present invention to provide pharmacological agents and formulations useful for the topical treatment of wounds and other disorders. Desirably, the compositions will be capable of providing a potent mitogenic activity which enhances the proliferation of epithelial cells, fibroblasts, and the like. The compositions should also be capable of stimulating the expression of extracellular matrices and development of cellular attachment mechanisms which contribute to normal morphology in the healed tissue. Preferably, the compositions should be capable of enhancing or modulating the growth promoting activity of other growth promotants. The compositions should be suitable for topical application to the skin and body organs, including the eye and should further be suitable for incorporation into a wide variety of delivery vehicles.
2. Description of the Background Art
Substance P
Substance P and substance K have been found to provide enhanced proliferation in cell cultures of smooth muscle cells and human skin fibroblasts (Nilsson et al. (1985) Nature 315: 6; Nilsson et al. (1986) Biochem. Biophys. Res. Comm. 137: 167; and Payan (1985) Biochem. Biophys. Res. Comm. 130: 104). Substance P enhances proliferation of human T-lymphocytes (Payan et al. (1983) J. Immunol. 131: 1613), and such enhancement is mediated by specific receptors for substance P (Payan et al. (1984) J. Immunol. 133: 3260). Substance P has also been found to stimulate the release of prostaglandin E.sub.2 (PGE.sub.2) from and enhance the proliferation of rheumatoid synoviocytes (Lotz et al. (1987) Science 235: 893). See also, Zachary et al. (1987) Dev. Bio. 124: 295. Substance P has been identified in developing ocular tissue by immunofluorescence (Sakiyama et al. (1984) Brain Research 315: 275). Systemic capsaicin treatment blocks the activity of substance P in animal models and can cause corneal ulcers (Shimizu et al. (1984) Naunyn-Schmiedeberg's Arch Pharmacol. 326: 347; Gamse et al. (1981) Naunyn-Schmied. Arch. Pharm. 317: 140; Tervo (1981) Acta Ophthal. 59: 737; Lembeck et al. (1981) Naunyn-Schmied. Arch. Phar. 316: 240; Gamse et al. (1986) Neuroscience Lett. 64: 287; and Tanaka et al. (1985) J. Cellular Physiol. 123: 191). Substance P and other tachykinins receptors are described in Quirion and Dam in: Substance P Metabolism and Biological Actions, Jordan and Oehme, eds., Taylor & Francis, London, 1985, Ch. 4., the disclosure of which is incorporated herein by reference.